In-vitro Dissolution, Bioavailability, Bio equivalence, Evaluation Noyes- Whitney Equation Interpretation of Dissolution Data Dissolution Apparatus

1. PERFORMANCE
EVALUATION METHODS
In-vitro Dissolution, Bioavailability, Bio equivalence,
Evaluation

2. In-vitro dissolution studies
Noyes- Whitney
Equation
Interpretation of
Dissolution Data

3. Factors affecting dissolution rate
 1. Disintegration is the important first step to drug dissolution in a tablet.
 2. Particle size of drug substance.
 3. Solubility and hydrophobicity of the drug; type and amount of disintegrant, diluent,
binder, lubricant, glidant and the coating type and thickness.
 4. Solubility and dissolution also influenced by pH of the media, media composition,
change in the crystalinity of drug, temperature, paddle speed.
 5. Manufacturing method (compactness of the granulation and compression force
used in tableting)

5. Dissolution Apparatus
Types:
On basis of USP
- Similarity and Dissimilarity Factor

6. Dissolution test apparatus
Stirrer shaft
Paddle Thermostated water bath
Glass vessel
USP apparatus II

7. Glass vessel 1000 ml volumeCylindrical Stainless
steal Basket formed
from a screen
Paddle
(USP apparatus II)
Stirrer shaft

8. Stirred vessel method
Basket type Paddle type

9. Media used in dissolution test:
- Purified water.
- Simulated gastric fluid.
- Simulated intestinal fluid.
- Solvents mixture may be used if the drug solubility is very low.
 Dissolution test is performed in-process and on the final product.

10. Bioavailability studies and bioavailability testing protocol and
procedures
Bioavailability - Bioequivalence

11. Bioavailability
Bioavailability is a pharmacokinetic
term that describes the rate and
extent to which the active drug
ingredient is absorbed from a drug
product and becomes available at
the site of drug action.
Why?
 Pharmacologic response is
generally related to the
concentration of drug at the
receptor site
 Quantity of Drugs in
blood/Urine need to be
estimated
 Assumption- Drug
concentration in blood is
equivalent to receptor site
concentration

12. Absolute Bioavailability
 Tofraction of an
administered dose which
actually reaches the
systemic circulation
 Denoted by F
 Ranges from F = 0 (no
drug absorption) to F = 1
(complete drug
absorption).

13. Relative Bioavailability
 Availability of a drug product
as compared to another
dosage form or product of the
same drug given in the same
dose.
 The relative bioavailability of
product A compared to
product B, both products
containing the same dose of
the same drug, is obtained by
comparing their respective

14. Relative Bioavailability
 When the bioavailability of
a generic product is
considered, it is usually the
relative bioavailability that
is referred to. A more
general form of the
equation results from
considering the possibility
of different doses:

15. Example

16. Factors affecting Bioavaliability
 disintegration of the drug product
 dissolution of the drug in the fluids at the
absorption site
 transfer of drug molecule across the
membrane lining the gastrointestinal tract into
the systemic circulation.

17. Factors affecting Bio-avaliability

18. Factors affecting Bio-avaliability

19. Bio-avaliability vs Rate of
absorption
 aqueous solution > aqueous suspension >
capsule> tablet > Controlled Released

20. Methods of assessing bioavailability-
Predicting Clinical efficacy
 Pharmacokinetics
 Pharmacodynamics

21. Methods of assessing bioavailability-
Predicting Clinical efficacy
 In vivo:
Single dose
Normal/healthy adult
Clinical performance- Large test population
Need to be validated,

22. Methods of assessing bioavailability-
Predicting Clinical efficacy
 Blood sampling
Parameters
1. AUC , The area under the plasma concentration-time curve, The
AUC is proportional to the total amount of drug reaching the
systemic circulation, and thus characterizes the extent of
absorption.
2. Cmax , The maximum drug concentration. The maximum
concentration of drug in the plasma is a function of both the rate
and extent of absorption. Cmax will increase with an increase in
the dose, as well as with an increase in the absorption rate.
3. Tmax , The time at which the Cmax occurs. The Tmax reflects the
rate of drug absorption, and decreases as the absorption rate
increases.

23. Methods of assessing bioavailability-
Predicting Clinical efficacy
 Urinary Excretion Data
-determination of the total quantity of drug excreted in the urine as a function
of time
- urinary excretion of the unchanged drug is directly proportional to the
plasma concentration of total drug.
- Consider the following example: two products, A and B, each containing
100 mg of the same drug are administered orally. A total of 80 mg of drug is
recovered in the urine from Product A, but only 40 mg is recovered from
Product B. This indicates that twice as much drug was absorbed from
Product A as from Product B. (The fact that neither product resulted in
excretion of the entire dose might be due to the existence of other routes of
elimination, e.g. metabolism).

24. Methods of assessing bioavailability-
Predicting Clinical efficacy
 Urinary Excretion Data
1. the fraction of drug entering the bloodstream
and being excreted intact by the kidneys
must remain constant.
2. collection of the urine has to continue until all
the drug has been completely excreted (five
times the half-life ).

25. Parameters for Urinary Excretion
1. Maximum urinary excretion
rate
2. Time for Maximum excretion
rate
3. Cumulative amount of Drug
excreted

26.  The assessment o bioavailability by urinary
excretion is based on the assumption that the
appearance of the drug and/ or its metabolites in
the urine is a function of the rate and extent o
absorption. This assumption is only valid when a
drug and/ or its metabolites are extensively
excreted in the urine, and where the rate of
urinary excretion is proportional to the
concentration o the intact drug in the blood
plasma.

27. Urinary Data

28. This proportionality does not hold
if:
 the drug and/ or its metabolites are excreted
by an active transport process into the distal
kidney tubule
 the intact drug and/ or its metabolites are
weakly acidic or weakly basic (i.e. their rate of
excretion is dependent on urine pH)
 the excretion rate depends on the rate o urine
flow.

29. Interpretation: Plasma concentration-time curves for three different
formulations of the same drug administered in equal single doses by the same
extravascular route.

30. Bio-Equivalence

31. Biopharmaceutics Classification
System
 Class I – high solubility/ high permeability
 Class II – low solubility/ high permeability
 Class III – high solubility/ low permeability
 Class IV – low solubility/ low permeability.

32. Topic End